Process of producing them



SUBSTITUTED AZACYCLOALKANES AND PROCESS OF PRODUCING THEM Julius Diamond, Philadelphia, and William F. Bruce,

Havertown, Pa., assignors to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Original application January 5, 1954, Serial No. 402,397, now Patent No. 2,740,779, dated April 3, 1956. Divided and this application June 28, 1955, Serial No. 518,652

3 Claims. (Cl. 260-439) This invention relates to the preparation of cyclic compounds and more particularly to the preparation of acyl azacycloalkanes. The present application is a division of application Serial No. 402,397, filed January 5, 1954, now Patent No. 2,740,779.

The compounds falling within the scope of the invention are specific members of the more general group of compounds disclosed and claimed in application Serial No. 297,185, filed July 3, 1952, now Patent No. 2,666,050. The present compounds may be represented by the general formula with R1 representing a lower alkyl and R2 standing for either hydrogen or an alkyl While A is an anion, R standing for an aryl group and with R3 and R4 each standing for hydrogen or lower alkyl and Rs representing a lower alkyl group.

With regard to R which represents an aryl radical, the latter may be either a substituted or unsubstituted phenyl ring. Preferred substituents on a ring which may be in any position and ranging from 1 to 3 are lower alkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl and acyloxy, amino and mono and di-lower alkylsubstituted amino radicals. As will be indicated later, an especially preferred radical because it imparts valuable therapeutic action to the compound is the m-hydroxy plienyl radical. In general, the compounds of the invention may be made in the manner disclosed in the earlier filed application Serial No. 297,185. A general procedure for making specific 4-acyl compounds utilizes the cyano compound obtained from reaction 3 disclosed in said earlier case. In such general procedure, an ether solution of the alkyl magnesium halide is prepared from 0.070 g.-atom of magnesium metal and 0.075 mole of alkyl halide in 100 ml. of dry ether. To this solution is added dropwise 0.05 mole of the appropriate 4-cyano compound in 100 ml. of toluene. The temperature is maintained, with stirring, at 2535 C. during the addition. On its completion, the temperature is gradually raised by distilling oif the ether. A maximum temperature of 65-85 C. is maintained for 6 hours. The mixture is cooled and extracted with dilute hydrochloric acid. The acid extract is Washed with ether, then basified with ammonium hydroxide, and finally extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate, filtered and concentrated. Vacuum distillation of the residue gives the desired aminoketone base.

Acid addition salts of the cyclic bases may be made in States Patent Q Well known manner as disclosed in application Serial No. 297,185 by reacting the appropriate base with the desired inorganic or organic carboxylic acid. Preferred acids are those mentioned in said prior application. These cyclic bases are also capable of reacting with'alkyl halides on an equimolar basis under normal conditions to form quaternary ammonium compounds.

The'reaction is carried out in the presence of inert solvent.

For a more specific description of the process, the following reactions illustrate the formation of the specitic compound 4-propionyl-4-m-hydroxyphenyl-l-methyl- 4-cyan0-4-m-meth0xyphenyl-N-methylazacycloheptane methochloride (Compound I!) A solution of 0.181 mole (39.5 g.) of Z-(m-methoxyphenyl)-4-dimethylamino-butyronitrile in 250 ml. of ether was added to a stirred suspension of 0.217 mole (8.5 g.) of sodamide in 250 ml. of ether at such a rate as to maintain gentle refluxing. The operations were carried out in a nitrogen atmosphere. Refluxing and stirring were continued for 2 additional hours. The mixture was cooled to 30 C., and 0.199 mole (31.5 g.) of trimethylene chlorobromide in ml. of ether was added dropwise at 25 C. to -l5 C. while stirring. The mixture was then allowed to warm to room temperature and stand overnight. The precipitated inorganic salts were filtered oil and the ether distilled from the filtrate at reduced pressure. The yellow liquid residue contained the 1,6- amino-chloride (I). This Was dissolved in ml. of benzonitrile and the resulting solution heated at 100 C. for 20 hours. The mixture was cooled, 180 ml. of acetone added, and the precipitated quaternary salt (II) was filtered otf after standing 4 hours. M. P. 212-213 C. dec.

Analysis.Calcd. for C16H23C1N2OZ C, 65.20; H, 7.86; N, 9.51; Cl, 12.03. Found: C, 65.15; H, 7.73; N, 9.51; Cl, 12.18.

' 4-cyarto-4wmmethoxypheriyl-N-methylazacycloheptane (Compound HI) Into a small Claisen flask set 11p for distillation, was placedv 0.085 mole. (25 g.) of the quaternary salt (II). After'evacuating the system to 1-3 mm., heat was applied using an air-bath. At a bath temperature of 200- 250 C. a liquid distilled over at 1702l0 C. Redistillation gave the cyano base (III), B. P. l50-154 C. (0.3 min), n 1.5332, (14 1.062.

Other compounds. falling within the scope of the in- V vention are givenin the following table with identifying characteristics. The various radicals R, R3, Rs and'Rs Analysis calcd for CHHZONZO: C 7370; H, 825; are specific species of the general formula given herein- N, 11.46; MD 71.18. Found: c, 74.27; H, 8.58; N, 11.12; MD 71.40. 30-00 R3 R4 4-propionyl-4-m-methoxyphenyl-N-methylazacyclo- R O OH H heptane (Compound IV) N'CHI Ethyl magnesium bromide was prepared from 0.09 OHZOHFCH B. P. R R3 R1 R5 (0.3 mm.), nu C.) derivative, M. P.

degreesoemnn H H C211 132-6 1.5302 (26)- {gg gfgg igf g ffl o rr nug H H 11-03111 132% 1.5300 (26) picrate,13840. COH5 H CH3 02H, 135-42 1.5350 (27.s) methlodide,1835. CGH5 on. H 02H. 123-42 1.5.100 27) picrate,1645d.

g.-atom (2.2 g.) of magnesium metal and 0.10 mole The-cyclic. free, bases. are useful for the formation. of (10.9 g.) of ethyl bromide in 150 ml. ether. To this quaternary ammonium. compounds since they readily resolution was added; with stirring, 0.0573 mole (14 g.) act with an alkyl halide, particularly the longchain alkyL of the cya-no base (III) in 150 ml. of ether at such a 30 halides, to form valuable wetting agents. These bases rate as' to maintain gentle refluxing. After 5 additional or their acid-addition. saltsare also capable of reacting hours of stirring and refluxing, the mixture was allowed with penicillin to form substantially water-insoluble'salts to stand overnight. The cooled mixture was extracted thereof. In addition, many of the bases or their salts with aqueous hydrochloric acid, the acid extract basified demonstrate varying degrees-of analgesic action and thus with ammonium hydroxide; extracted with ether, and the are useful therapeutics. ether extract. dried, filtered, and concentrated under re- We claim: duced pressure. A light yellow liquid residue remained l. The compound selected from the group consisting of which contained the crude ketobase (IV). an azacycloheptane havingthe formula 4-pr0pi0nyl-4-m-hydr0xyphenyl-N-methylazacycloheptane 40 if (Compound V) CQHPO R-C-OHr-OH-r The above Compound IV was used without further purification. It was dissolved'in 100 ml. of 48% hydrobromic acid. The solution was heated to reflux and kept OHZ-OHPCHa at this temperature (110-125 C.) for 17 hours. The and the acid-addition salts thereof; wherein R is a radical cooled solution was treated with 230 ml. of 4 N-sodium selected from the group consisting of m-methoxyphenyl hydroxide solution and the resulting solution Washed with and m-hydroxy-phenyl. ether. The aqueous alkaline solution was saturated with T ompound" 4'1'11-mcthoxyphenyl l propionyl-lcarbon dioxide to precipitate an oil which was extracted 50 mcihylazacycloheptanewith chloroform. The extract was dried, filtered,, and The compmmd Y YP Y 'P P Y distilled. At 190-200 C. 0.3 mm.) 3.3 g. of a yellow methylazacycloh'eptaneviscous syrup distilled over. On cooling the material became glassy. It was dissolved in boiling ether, filtered, References Clted mthe file of this patent and the filtrate concentrated to a small volume. 011 standingat room temperature, the product (V) appeared UNITED STATES PATENTS Diamond et al Jan. 12, 19-54 

1. THE COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN AZACYCLOHEPTANE HAVING THE FORMULA 